Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human...

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Bibliographic Details
Published in:Molecular biology reports 2012-07, Vol.39 (7), p.7743-7753
Main Authors: Xu, Tao, Wang, Nian-Song, Fu, Li-Li, Ye, Chao-Yang, Yu, Sheng-Qiang, Mei, Chang-Lin
Format: Article
Language:English
Subjects:
Animal Anatomy
Animal Biochemistry
Animals
Apoptosis
Apoptosis - drug effects
bcl-2-Associated X Protein
Biomedical and Life Sciences
Caspase 3 - biosynthesis
Celecoxib
Cell cycle
Cell Cycle Checkpoints - drug effects
Cell Proliferation - drug effects
Cells, Cultured
Cyclin A - biosynthesis
Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis
Cyclooxygenase 2 Inhibitors - pharmacology
Cysts
Cysts - drug therapy
Disease Models, Animal
Epithelial Cells - drug effects
Extracellular Signal-Regulated MAP Kinases - metabolism
Gene expression
Histology
Humans
Kidney diseases
Life Sciences
Male
MAP Kinase Signaling System - drug effects
Morphology
Pharmacology
Polycystic Kidney Diseases - drug therapy
Polycystic Kidney Diseases - metabolism
Polycystic Kidney Diseases - pathology
Pyrazoles - pharmacology
raf Kinases - antagonists & inhibitors
raf Kinases - metabolism
Rats
Sulfonamides - pharmacology
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
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Summary:Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human ADPKD cyst-lining epithelial cells. Primary cultures of ADPKD cyst-lining epithelial cells were obtained from five patients. Effects of CXB were measured by various assays to detect BrdU incorporation, apoptosis and proliferation in vitro. Additionally, effects of CXB on kidney weight, the cyst index, the fibrosis index, blood urea nitrogen (BUN), serum creatinine (SCr), serum 6-keto-PGF-1α, serum thromboxane-2 (TXB2) and renal PCNA expression were assessed in Han:SPRD rat, a well-characterized rodent model of PKD. CXB inhibited proliferation of ADPKD cyst-lining epithelial cells, blocked the release of VEGF from the cells and induced extensive apoptosis in a time- and dose-dependent manner. Moreover, CXB up-regulated the cell cycle negative regulator p21 CIP/WAF1 and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation, induced apoptotic factors (Bax and caspase-3) and reduced Bcl-2. Furthermore, CXB inhibited the expression of VEGFR-2 and Raf-1 in ADPKD cyst-lining epithelial cells. CXB markedly reduced the cyst index, the fibrosis index, leukocyte infiltration, BUN, SCr, serum 6-keto-PGF-1α, TXB2 and renal PCNA expression in Han:SPRD rat. We demonstrated for the first time that CXB could suppress renal cyst-lining growth both in vitro and in vivo in Han:SPRD rat. CXB can inhibit proliferation, suppress cell cycle progression, and induce apoptosis in ADPKD cyst-lining epithelial cells through the inhibition of the VEGF/VEGFR-2/Raf-1/MAPK/ERK signaling pathway.
ISSN:0301-4851
1573-4978
DOI:10.1007/s11033-012-1611-2